Phase 2 Multicenter Trial of Oral Quisinostat, a Histone Deacetylase Inhibitor, in Patients with Previously Treated Stage IB-IVA Cutaneous T-Cell Lymphoma

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3676-3676 ◽  
Author(s):  
Fiona Child ◽  
Pablo Ortiz Romero ◽  
Rute Alvarez ◽  
Martine Bagot ◽  
Rudolf Stadler ◽  
...  
Keyword(s):  
Research Funding ◽  
Dose Group ◽  
Cell Lymphoma ◽  
Cutaneous T Cell Lymphoma ◽  
Efficacy And Safety ◽  
Employment Equity ◽  
Stage Ib ◽  
Secondary Endpoints ◽  
Previously Treated ◽  
Equity Ownership

Abstract Abstract 3676 Background Mycosis fungoides (MF) and Sézary syndrome (SS) represent two major instances of cutaneous T-cell lymphoma (CTCL), which are incurable and have shown response to treatment with histone deacetylase (HDAC) inhibitors. Quisinostat is a potent and orally active HDAC inhibitor that has been found to be active in preclinical models and phase 1 trials. The purpose of this phase 2 trial (NCT01486277) is to evaluate the efficacy and safety of quisinostat in patients with previously treated advanced stage IB-IVA MF or SS. Patients and Methods Patients with relapsed or refractory, measurable, histopathologically confirmed CTCL, stages IB to IVA MF/SS, were treated with 8mg or 12 mg of oral quisinostat on days 1, 3 and 5 of each week in a 21-day treatment cycle. Patients who were initially randomized to the 8 mg dose cohort and did not have evidence of disease progression were allowed to have their dose increased to 12 mg. The primary efficacy endpoint was the overall cutaneous response rate (RR) measured by the modified Severity Weighted Assessment Tool (mSWAT). Key secondary endpoints included overall global RR, progression-free survival (PFS), 1-year overall survival (OS) rate, duration of response (DOR), and patient-reported outcome (PRO) which included the European Organization for Research and Treatment of Cancer Core (EORTC) questionnaire QLQ-C30 and the Pruritus Intensity Assessment questionnaire. Other secondary endpoints were pharmacodynamic markers, biomarkers predictive of response, and population pharmacokinetics (PK). Safety and tolerability have also been evaluated. Results Twenty-six patients were enrolled, including 6 patients in the 8 mg dose group and 20 patients in the 12 mg dose group. One patient in the 12 mg dose group discontinued prematurely from the study due to investigator's decision, and was therefore excluded from the response evaluable analysis set. Overall, enrolled patients included 81% male; median age = 61 years (range 32–80 years); 96% white; MF/SS stage: IB/IIA = 35% (n=9) and IIB/III/IVA = 65% (n=17); CTCL type: MF = 96% (n=25), and SS = 4% (n=1); mean Pruritus Intensity Score = 5.1. The preliminary results of this ongoing trial have shown that 6 out of 19 patients (31.6%) in the 12 mg dose group achieved ≥ 50% reduction in mSWAT score at least once, with confirmed response in the skin in 4 patients (1 complete response (CR) and 3 partial response (PR); overall RR = 21.1% with 95% CI: 6.1% to 45.6%). For the other 2 patients, the confirmation of response is pending in 1 patient and the other patient stopped the treatment due to non-drug related adverse event (AE). Nine patients are still on the treatment with the 12 mg dose, and 11 patients have discontinued the drug (6 due to progressive disease (PD), 2 due to investigator's decision, 2 due to AE, and 1 due to death). In the 8 mg dose group, no CR or PR in the skin has been observed, and 4 out of 6 patients have discontinued due to PD. The secondary endpoint results of overall global RR, PFS, 1-year OS rate, DOR, and PROs, as well as biomarker results for AcH3, ac-Tubulin, Cleaved Caspase 3, HR23B and pStat3, will be presented when further analysis results are available. To date, the most common (≥ 5% of patients) drug-related AEs have been nausea (23%), diarrhea (19%), asthenia (12%), thrombocytopenia (12%), hypertension (8%), lethargy (8%), palpitations (8%), pruritus (8%) and vomiting (8%); most of them were grade 2 or lower in severity. Grade 3 or higher AEs included hypertension (4%), lethargy (4%), pyrexia (4%), and hyperkalaemia (4%). One patient in the 8 mg dose group has required dose reduction due to hypertension. The efficacy and safety results from the final analysis will be presented. Conclusion Preliminary results indicate that oral quisinostat at 12 mg dose on a 3 times weekly schedule is active in the treatment of patients with relapsed or refractory MF/SS not previously treated with an HDAC inhibitor, and has an acceptable safety profile. Disclosures: Child: Cephalon UK : Honoraria; Janssen R&D: Research Funding. Ortiz Romero:Ferrer Farma SA: Honoraria; Eisai: Honoraria. Weichenthal:Merck Inc.: Consultancy, Honoraria. Bernengo:Janssen R&D: Research Funding; NOVARTIS: Research Funding. Pérez Ferriols:Pfizer: Consultancy, Honoraria, Research Funding. Hellemans:Janssen R&D: Employment, Equity Ownership. Elsayed:Janssen R&D: Employment, Equity Ownership. Phelps:Janssen R&D: Employment, Equity Ownership. Forslund:Janssen R&D: Employment. Kamida:Janssen R&D: Employment. Zinzani:Millennium Takeda: Consultancy; Celgene: Consultancy.

The Bruton's Tyrosine Kinase Inhibitor PCI-32765 Is Highly Active As Single-Agent Therapy in Previously-Treated Mantle Cell Lymphoma (MCL): Preliminary Results of a Phase II Trial

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 442-442 ◽  
Author(s):  
Luhua Wang ◽  
Peter Martin ◽  
Kristie A. Blum ◽  
Brad S. Kahl ◽  
Lauren S. Maeda ◽  
...  
Keyword(s):  
B Cell ◽  
Phase Ii ◽  
Research Funding ◽  
Phase Ii Trial ◽  
Cell Lymphoma ◽  
Single Agent ◽  
Employment Equity ◽  
Mantle Cell ◽  
Previously Treated ◽  
Equity Ownership

Abstract Abstract 442 Introduction: Bruton's tyrosine kinase (Btk) is a central mediator of B-cell receptor signaling which is essential for normal B-cell development. PCI-32765 is an orally administered irreversible inhibitor of Btk that induces apoptosis and inhibits cellular migration and adhesion in malignant B-cells. In a phase I trial of PCI-32765 in relapsed B-cell malignancies, objective responses were observed in seven of nine patients with MCL. Reported here are preliminary results of an ongoing phase II study of single-agent PCI-32765 in previously treated MCL. Methods and Patients: Patients with relapsed or refractory MCL who were either bortezomib-naïve or bortezomib-exposed (prior treatment with at least 2 cycles of bortezomib) were eligible for study PCYC-1104. PCI-32765 was administered orally at 560mg daily (in continuous 28-day cycles) until disease progression. Bortezomib-naive and bortezomib-exposed cohorts were evaluated separately. Tumor response was evaluated every 2 cycles and classified by 2007 NHL IWG criteria. Results: A total of 48 patients (29 bortezomib-naive, 19 bortezomib-exposed) have been enrolled on study PCYC-1104 between February 16, 2011 and July 20, 2011. The median age is 67 years (62–72). The median number of prior treatment regimens is 2 (1–5). Five patients (13%) had received prior autologous or allogeneic stem cell transplantation. Seven patients (15%) had bulky disease. Thirty-nine patients who have initiated treatment and have reported adverse event (AE) information are the subject of this preliminary report. Twenty-four patients (12 bortezomib-naive, 12 bortezomib-exposed) have undergone at least 1 follow-up tumor assessment and are evaluable for efficacy. Treatment has been well tolerated. No patients have discontinued treatment due to AEs. Grade 1 or 2 diarrhea, fatigue, and nausea have been the most frequently reported AEs. Grade >3 AEs considered potentially related to PCI-32765 have occurred in 4/39 patients (11%). Serious AEs (SAEs) have occurred in 8/39 patients (21%); 2 SAEs (1 rash, 1 febrile neutropenia) were considered potentially related to PCI-32765. One death, in a patient who was enrolled but did not receive PCI-32765 due to rapid disease progression, has occurred on study. The objective response rate (ORR) by IWG criteria is 67% (16/24); ORR is 58% (7/12) in the bortezomib-naive cohort and 75% (9/12) in the bortezomib-exposed cohort. To date, 35/39 patients remain on PCI-32765; reasons for discontinuation include progressive disease (n=3) and investigator decision (n=1). Conclusions: Preliminary data from a phase II trial suggests that the potent Btk inhibitor PCI-32765 is well tolerated and induces a high rate of objective responses in patients with relapsed or refractory MCL. More mature safety and efficacy data will be updated in the presentation. Phase III trials of PCI-32765 in MCL are planned. Disclosures: Wang: Pharmacyclics: Research Funding. Off Label Use: PCI-32765 in mantle cell lymphoma in a phase 2 clinical trial. Martin:Pharmacyclics: Research Funding. Blum:Pharmacyclics: Research Funding. Kahl:Pharmacyclics: Research Funding. Maeda:Pharmacyclics: Research Funding. Advani:Pharmacyclics: Research Funding. Williams:Pharmacyclics: Research Funding. Rule:Pharmacyclics: Research Funding. Rodriguez:Pharmacyclics: Employment, Equity Ownership. Pang:Pharmacyclics: Consultancy. Hedrick:Pharmacyclics: Employment, Equity Ownership. Goy:Pharmacyclics: Research Funding.

A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and Safety of Idelalisib and Rituximab for Previously Treated Patients with Chronic Lymphocytic Leukemia (CLL)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. LBA-6-LBA-6 ◽  
Author(s):  
Richard R. Furman ◽  
Jeff P. Sharman ◽  
Steven E. Coutre ◽  
Bruce D. Cheson ◽  
John M. Pagel ◽  
...  
Keyword(s):  
Odds Ratio ◽  
Research Funding ◽  
Single Agent ◽  
Efficacy And Safety ◽  
Employment Equity ◽  
Phase 3 ◽  
Advisory Committees ◽  
Heavily Pretreated ◽  
Previously Treated ◽  
Equity Ownership

Abstract Background Idelalisib (IDELA) is a first-in-class, selective, oral inhibitor of PI3Kδ that reduces proliferation, enhances apoptosis, and inhibits homing and retention of malignant B cells in lymphoid tissues. Phase 1 trials demonstrated that IDELA is highly active as a single agent or in combination with rituximab (R) in heavily pretreated patients (pts) with CLL. Pts in these trials experienced reductions in disease-associated chemokines, improvement of organomegaly and cytopenias, profound reductions in lymphadenopathy, and durable clinical benefit with an acceptable safety profile (Brown 2013; Barrientos 2013). Patients with early progression and significant co-morbidities have limited treatment options; single-agent rituximab is an option in these pts (NCCN 2013; Zelenetz 2013). Methods This Phase 3 study evaluated the efficacy and safety of IDELA + R vs placebo + R in pts with previously treated CLL. Eligibility criteria included the need for treatment per IWCLL guidelines, measurable lymphadenopathy, and CLL progression <24 mos since the completion of last therapy. Pts were considered unfit to receive cytotoxic therapy because of comorbidities (defined as a Cumulative Illness Rating Score [CIRS] > 6), renal dysfunction, or cytopenias due to poor marrow reserve. All pts received R at 375 mg/m2 [1st dose] and then 500 mg/m2q2 wks x 4, followed by q4 wks x 3 [8 doses total]) and were randomized to Arm A (n=110; IDELA 150 mg BID continuously) or Arm B (n=110; placebo BID continuously). Primary endpoint was progression-free survival (PFS). Response and progression in both arms were assessed by an independent review committee using standard criteria (Hallek 2008; Cheson 2012). Results were reviewed by an external Data Monitoring Committee (DMC). Results Results are from a pre-specified interim analysis after ∼50% of the total number of 119 planned events of CLL progression or death from any cause. Data cutoff was 30 Aug 2013. Pt characteristics (n=220) included a median age of 71 yrs (78% ≥ 65 yrs); CIRS > 6 in 85%; median creatinine clearance of 63.6 mL/min; and presence of anemia (73%), thrombocytopenia (61%), neutropenia (34%). Median time since diagnosis was 8.5 yrs, median number of prior therapies was 3 (range: 1-12), 44% had del(17p)/TP53 mutation, and 84% had unmutated IGHV. PFS in the IDELA + R arm was superior to placebo +R (HR [95% CI] = 0.15 [0.08, 0.28]; p = 3.0 x 1011). Median PFS of pts treated with IDELA + R was not reached and for placebo + R was 5.5 mos. At 24 wks, the PFS rate for IDELA +R was 93% compared to 46% for placebo + R. PFS strongly favored IDELA + R in all subgroups, including those with del(17p)/TP53 or unmutated IGHV. Pts treated with IDELA + R and with ≥1 post-baseline assessment also had a superior overall response rate (ORR) relative to those in the control arm (81% vs. 13%; odds ratio 29.9; p = 3.0 x 1019) and a higher lymph node response (LNR) rate (93% vs. 4%; odds ratio 264.5; p = 1.3 x 10-30). Relative to the control group, pts treated with IDELA +R also had a significant improvement in overall survival (OS): HR (95% CI) = 0.28 (0.09, 0.86), p = 0.018. Adverse events (AEs) occurring in ≥20% of pts (any Gr/Gr ≥3) by arm were: pyrexia (IDELA + R 29%/3%; placebo + R 16%/1%), fatigue (IDELA + R 24%/3%; placebo + R 27%/2%), nausea (IDELA + R 24%/0%; placebo + R 22%/0%), chills (IDELA + R 22%/2%; placebo + R 16%/0%), infusion-related reactions (IDELA + R 16%/0%; placebo + R 28%/4%), and cough (IDELA + R 15%/0%; placebo + R 25%/2%). Other selected AEs (any Gr/Gr ≥3) included diarrhea (IDELA + R 19%/4%; placebo + R 14%/0%) and rash (IDELA + R 10%/2%; placebo + R 6%/0%). Select lab abnormalities (any Gr/Gr ≥3) included ALT elevation (IDELA + R 31%/6%; placebo + R 9%/1%), anemia (IDELA + R 26%/6%; placebo + R 30%/14%), neutropenia (IDELA + R 55%/34%; placebo + R 49%/22%), and thrombocytopenia (IDELA + R 17%/10%; placebo + R 26%/16%). The most common SAEs were pneumonia (6.4%), pyrexia (6.4%), and febrile neutropenia (4.5%) in IDELA + R, and pneumonia (8.4%), febrile neutropenia (5.6%), and dyspnea (3.7%) in placebo + R. AEs led to study drug discontinuation in 9 pts (8.2%) in IDELA + R and 11 pts (10.3%) in placebo + R. Based on a review of efficacy and safety, the DMC recommended stopping the study early. Conclusions IDELA + R demonstrated statistically significant improvement with acceptable safety over placebo + R in PFS, ORR, LNR and OS in heavily pretreated pts with relapsed CLL, including those with adverse genetic features. Disclosures: Furman: Gilead Sciences: Research Funding. Sharman:Gilead Sciences: Consultancy, Research Funding. Coutre:Gilead Sciences: Research Funding. Cheson:Gilead Sciences: Research Funding. Pagel:Gilead Sciences: Research Funding. Hillmen:Gilead Sciences: Research Funding. Barrientos:Gilead Sciences: Research Funding. Zelenetz:Gilead Sciences: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Kipps:Gilead Sciences: Research Funding. Flinn:Gilead Sciences: Research Funding. Ghia:Gilead Sciences: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Eradat:Gilead Sciences: Research Funding. Ervin:Gilead Sciences: Research Funding. Lamanna:Gilead Sciences: Research Funding. Hallek:Gilead Sciences: Research Funding. Coiffier:Gilead Sciences: Research Funding. Pettitt:Gilead Sciences: Research Funding. Ma:Gilead Sciences: Research Funding. Stilgenbauer:Gilead Sciences: Honoraria, Research Funding. Aiello:Gilead Sciences: Employment. Johnson:Gilead Sciences: Employment, Equity Ownership. Miller:Gilead Sciences: Employment, Equity Ownership. Li:Gilead Sciences: Employment. Jahn:Gilead Sciences: Employment. Dansey:Gilead Sciences: Employment, Equity Ownership. O'Brien:Gilead Sciences: Research Funding.

Efficacy and Safety of Ponatinib According to Prior Approved Tyrosine Kinase Inhibitor (TKI) Therapy in Patients with Chronic Myeloid Leukemia in Chronic Phase (CP-CML): Results From the PACE Trial

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3749-3749
Author(s):  
Dong-Wook Kim ◽  
Jorge E. Cortes ◽  
Javier Pinilla-Ibarz ◽  
Philipp le Coutre ◽  
Ronald Paquette ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Response Rates ◽  
Efficacy And Safety ◽  
Employment Equity ◽  
Advisory Committees ◽  
Kaplan Meier ◽  
Previously Treated ◽  
Equity Ownership

Abstract Abstract 3749 Background: Ponatinib is a potent pan-BCR-ABL inhibitor that is active against native and mutated forms of BCR-ABL, including the uniformly TKI-resistant T315I mutant. The efficacy and safety of ponatinib (45 mg orally once daily) in patients with CP-CML were evaluated in a pivotal phase 2, international, open-label clinical trial. Objectives: This prospectively defined analysis was performed to evaluate the impact that previous exposure to approved TKIs had on the efficacy and safety of ponatinib treatment among patients with CP-CML. Methods: The PACE trial enrolled 449 patients, including 270 patients with CP-CML. Enrolled patients were required to be resistant or intolerant (R/I) to dasatinib or nilotinib, or they had to have the T315I mutation at baseline. Patients with CP-CML were assigned to 1 of 2 cohorts: R/I (N=203) or T315I (N=64). Three patients were post-imatinib and did not have T315I at baseline; they were treated but not assigned to a cohort. The primary endpoint was major cytogenetic response (MCyR) at any time within 12 months after treatment initiation. The trial is ongoing. Data as of 23 July 2012 are reported, with a minimum follow-up of 9 months (median 12 [0.1 to 19] months). The efficacy and safety of ponatinib according to prior approved TKI therapy (imatinib, dasatinib, nilotinib) is presented for the total CP-CML (N=270) population. Results: The median age of CP-CML patients was 60 (18 to 94) years. Median time from initial diagnosis to start of ponatinib was 7 (0.5 to 27) years. Patients were heavily pretreated: 97% had received prior imatinib, 80% dasatinib, 68% nilotinib; 7% of patients had received 1 prior approved TKI, 40% 2 prior approved TKIs, 53% all 3 prior approved TKIs; 60% had received ≥3 prior approved/investigational TKIs. In patients previously treated with dasatinib or nilotinib (N=256), 84% had a history of resistance and 16% were purely intolerant to dasatinib or nilotinib. At the time of analysis, 66% of patients remained on study. The most common reasons for discontinuation were adverse events (AEs; 12%) and progressive disease (7%). Response rates according to the number of prior approved TKIs are shown in the table below. Patients receiving fewer prior approved TKIs had higher response rates. The difference in MCyR rate was statistically significant for patients previously treated with 1 vs. 3 approved TKIs (p=0.003) and for patients previously treated with 2 vs. 3 approved TKIs (p=0.011). Differences in MMR rates were not statistically significant. Of patients achieving MCyR, 98% of patients receiving 2 prior approved TKIs and 83% of patients receiving 3 prior approved TKIs were predicted (Kaplan-Meier) to remain in MCyR at 1 year. Of patients achieving MMR, 86% of patients receiving 2 prior approved TKIs and 80% of patients receiving 3 prior approved TKIs were predicted (Kaplan-Meier) to remain in MMR at 1 year. Kaplan-Meier estimates were not calculable for patients receiving 1 prior TKI. The most common treatment-related AEs according to number of prior approved TKIs (1, 2, 3, respectively) were thrombocytopenia (32%, 38%, 44%), rash (37%, 37%, 39%), dry skin (37%, 36%, 39%), abdominal pain (21%, 26%, 28%), and headache (26%, 28%, 19%). Rash, dry skin, abdominal pain, and headache were generally grade 1 or 2 in severity. Thrombocytopenia was typically reported early in treatment and was manageable with or without dose reductions and/or dose interruptions. Conclusions: Ponatinib has substantial activity in patients with CP-CML, with higher response rates and improved tolerability observed in patients receiving fewer prior approved TKIs. Data with a minimum follow-up of 12 months will be presented. Disclosures: Kim: Novartis, BMS, Pfizer, ARIAD, and Il-Yang: Consultancy, Employment, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Cortes:Novartis, BMS, ARIAD, Pfizer, and Chemgenex: Consultancy, Research Funding. Pinilla-Ibarz:Novartis, BMS: Research Funding, Speakers Bureau. le Coutre:Novartis and BMS: Honoraria. Paquette:ARIAD: Consultancy. Chuah:Novartis and Bristol Myers-Squibb: Honoraria. Nicolini:Novartis, Bristol Myers Squibb, Pfizer, ARIAD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Apperley:Novartis, Bristol Myers-Squibb, and ARIAD: Honoraria, Research Funding. Talpaz:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millenium: Research Funding; Celgene: Research Funding; ARIAD: Research Funding; Deciphera: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees. Abruzzese:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees. Rea:Bristol Myers-Squibb, Novartis, and Teva: Honoraria. Baccarani:ARIAD, Novartis, Bristol Myers-Squibb, and Pfizer: Consultancy, Honoraria, Speakers Bureau. Muller:ARIAD: Consultancy. Wong:MolecularMD Corp: Employment, Equity Ownership. Lustgarten:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Rivera:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Clackson:ARIAD: Employment, Equity Ownership. Turner:ARIAD: Employment, Equity Ownership. Haluska:ARIAD: Employment, Equity Ownership. Guilhot:ARIAD: Honoraria. Hochhaus:ARIAD, Novartis, Bristol Myers-Squibb, Pfizer, and MSD: Membership on an entity's Board of Directors or advisory committees, Research Funding. Hughes:Novartis, BMS, ARIAD: Honoraria, Research Funding. Goldman:Novartis, Bristol Myers-Squibb, and Amgen: Honoraria. Shah:ARIAD: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy. Kantarjian:Pfizer: Research Funding; BMS: Research Funding; Novartis: Consultancy, Research Funding; ARIAD: Research Funding.

scholarly journals Ibrutinib Vs Temsirolimus: Results from a Phase 3, International, Randomized, Open-Label, Multicenter Study in Patients with Previously Treated Mantle Cell Lymphoma (MCL)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 469-469 ◽  
Author(s):  
Simon Rule ◽  
Wojciech Jurczak ◽  
Mats Jerkeman ◽  
Rodrigo Santucci ◽  
Chiara Rusconi ◽  
...  
Keyword(s):  
Research Funding ◽  
Cell Lymphoma ◽  
Phase 2 ◽  
Open Label ◽  
Employment Equity ◽  
Phase 3 ◽  
Once Daily ◽  
Previously Treated ◽  
Equity Ownership ◽  
To Receive

Abstract Introduction MCL is an aggressive B-cell lymphoma with a poor overall prognosis. For patients who fail initial therapy, conventional chemotherapy achieves only short-term remissions. Ibrutinib is a first-in-class, once-daily, oral, covalent inhibitor of Bruton's tyrosine kinase that has been shown to be highly active for previously treated MCL patients (overall response rate [ORR] ~65%; complete response [CR] ~20%) in single-arm phase 2 studies. Temsirolimus has demonstrated significantly longer progression-free survival (PFS) vs investigator's choice. In this phase 3, randomized, open-label study (MCL3001 [RAY]), ibrutinib was compared with temsirolimus in patients with relapsed or refractory (R/R) MCL who had received ≥1 prior rituximab-containing therapy. Methods Patients were randomized at a 1:1 ratio to receive oral ibrutinib (560 mg once-daily) or intravenous temsirolimus (175 mg: Days 1, 8, and 15 of Cycle 1; 75 mg: Days 1, 8, and 15 of subsequent cycles). Stratification factors were number of prior lines of therapy (1-2 vs ³3) and simplified MCL international prognostic index (sMIPI) risk (low [0-3] vs intermediate [4-5] vs high [6-11]). Patients in both arms received treatment until disease progression or unacceptable toxicity. Primary end point of the study was PFS, as assessed by an independent review committee (IRC). Secondary end points included ORR, overall survival (OS), time to next treatment (TTNT), time to worsening of lymphoma symptoms (measured by FACT-Lym lymphoma subscale), and safety. Results Overall, 280 patients were randomized to ibrutinib (n = 139) or temsirolimus (n = 141). Baseline disease characteristics and demographics were generally well balanced. Median age (range) was 68 years (34-88) and median number (range) of prior lines of therapy was 2 (1-9). Approximately two-thirds of the patients had intermediate- or high-risk disease. At the time of this analysis, median follow-up was 20.0 months. Ibrutinib was superior to temsirolimus for the primary end point of IRC-assessed PFS, with a statistically significant 57% reduction in the risk of progression or death (Figure 1). The median PFS was 14.6 months for the ibrutinib arm and 6.2 months for the temsirolimus arm, respectively. At a landmark of 2 years, the PFS rate is 41% in the ibrutinib arm vs 7% in the temsirolimus arm. PFS results were consistent across most assessed subgroups. Investigator-assessed PFS was consistent with the IRC results. IRC-assessed ORR was significantly higher for ibrutinib vs temsirolimus (71.9% vs 40.4%; p < 0.0001) with a CR rate of 18.7% vs 1.4%, respectively. Median OS was not reached with ibrutinib vs 21.3 months with temsirolimus, showing a positive trend toward patients in the ibrutinib arm (reduced risk of death by 24% [HR, 0.76; 95% CI, 0.53-1.09]). However, these results may have been confounded by 23% of patients that initially received temsirolimus crossing over to receive ibrutinib. A greater proportion of patients treated with ibrutinib vs temsirolimus avoided worsening of lymphoma symptoms throughout the study; 27% of ibrutinib patients had worsening vs 52% of temsirolimus patients. Median TTNT was not reached with ibrutinib vs 11.6 months with temsirolimus. Median treatment duration was 14.4 months for ibrutinib and 3.0 months for temsirolimus. Overall, 6.5% of subjects discontinued treatment due to AEs in the ibrutinib arm and 25.5% of subjects discontinued treatment due to AEs in the temsirolimus arm. The most common TEAEs with ibrutinib were diarrhea, fatigue, and cough, whereas with temsirolimus, thrombocytopenia, anemia, and diarrhea were most commonly observed (Table 1). Grade ³3 TEAEs were reported for 67.6% of ibrutinib patients vs 87.1% of temsirolimus patients; most frequent were thrombocytopenia, anemia, and neutropenia. When adjusted for exposure, TEAE incidence was consistently lower for the ibrutinib arm vs the temsirolimus arm. Conclusions Ibrutinib is superior to temsirolimus for PFS and ORR, and showed preferable tolerability. The results of this phase 3 trial confirm the efficacy and favorable safety profile of ibrutinib shown in phase 2 studies. Future concepts will investigate ibrutinib-based combination approaches for patients with R/R MCL. Disclosures Rule: Gilead: Research Funding; Celgene: Consultancy, Other: Travel reimbursement; J&J: Consultancy, Other: Travel reimbursement, Research Funding; Roche: Consultancy, Other: Travel reimbursement. Rusconi:Roche: Honoraria. Joao:Celgene, Novartis: Consultancy; Janssen, Roche: Membership on an entity's Board of Directors or advisory committees. Witzens-Harig:Pfizer: Honoraria, Research Funding; Roche: Honoraria. Hess:Pfizer, Janssen, Roche, Mundipharma: Honoraria, Research Funding; Janssen, Roche, , Celgene, Novartis: Consultancy. Balasubramanian:Janssen: Employment, Equity Ownership; Pharmacyclics LLC, an AbbVie Company: Equity Ownership. Bandyopadhyay:Janssen: Employment. Sun:Janssen/J&J: Employment, Equity Ownership. Goldberg:Janssen: Employment. Bothos:Janssen: Employment. Traina:Janssen: Employment. Enny:Janssen: Employment. Rizo:Janssen: Employment. Vermeulen:Janssen: Employment.

Safety and Tolerability of Conatumumab in Combination with Bortezomib or Vorinostat in Patients with Relapsed or Refractory Lymphoma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1708-1708 ◽  
Author(s):  
Anas Younes ◽  
Mark Kirschbaum ◽  
Lubomir Sokol ◽  
Lorrin Yee ◽  
Jorge Romaguera ◽  
...  
Keyword(s):  
Research Funding ◽  
Cell Lymphoma ◽  
Death Receptor ◽  
Large Cell ◽  
Employment Equity ◽  
Expansion Phase ◽  
Mantle Cell ◽  
Equity Ownership ◽  
Refractory Lymphoma ◽  
Grade 3

Abstract Abstract 1708 Poster Board I-734 Conatumumab is an investigational, fully human, monoclonal antibody agonist of human death receptor 5 (DR5 [TRAIL receptor 2]) that activates caspases and triggers apoptosis in sensitive tumor cells. DR5 is expressed by a variety of lymphoma cell lines, and TRAIL receptor agonists have been shown to induce apoptosis in lymphoma cells and lymphoma xenografts. Bortezomib and vorinostat are active and approved agents in certain lymphoma subtypes. In addition, they enhance death receptor-mediated apoptosis in multiple tumor models. In this 2-part study, we evaluated conatumumab in combination with bortezomib or vorinostat to treat patients (pts) with relapsed or refractory lymphoma. The dose-escalation phase evaluated the safety and tolerability of escalating doses of conatumumab in combination with bortezomib or vorinostat; the dose-expansion phase was designed to estimate the efficacy of conatumumab plus bortezomib in pts with mantle cell lymphoma (MCL). Here we present data from the dose-escalation phase. Eligibility criteria included: relapsed or refractory low-grade lymphoma, mantle cell lymphoma (MCL), diffuse large cell lymphoma, or Hodgkin lymphoma; age ≥ 18 years; informed consent; ECOG performance status of 0 or 1; life expectancy of > 3 months; adequate organ function; no prior treatment with bortezomib or vorinostat; no evidence of CNS involvement by lymphoma; and no primary CNS lymphoma. Three to 6 pts were enrolled into 1 of 3 sequential dose cohorts (1.5, 5, or 15 mg/kg) of conatumumab administered intravenously every 3 weeks (on day 1 of every 21-day cycle) in combination with either bortezomib (1.3 mg/m2 IV twice weekly for 2 weeks followed by a 10-day rest period) or vorinostat (400 mg orally daily). Endpoints included safety, maximum tolerated dose (MTD) of conatumumab, pharmacokinetics (PK) of conatumumab, incidence of anti-conatumumab antibodies, and best tumor response (complete response [CR] and partial response [PR]). CRs were confirmed by FDG-PET and bone marrow biopsy per Cheson criteria (2007). Monocyte DR5 occupancy by conatumumab was determined as an exploratory endpoint. As of July 9, 2009, 27 pts were enrolled and 23 received ≥1 dose of conatumumab: 3, 3, and 6 pts at 1.5, 5, and 15 mg/kg conatumumab + bortezomib; 7, 3, and 1 pt at 1.5, 5, and 15 mg/kg conatumumab + vorinostat. 15 pts were men; median (range) age was 53 (23 to 81) years; ECOG PS 0 = 65%, 1 = 26%, unknown = 9%; disease stage I = 4%, II = 4%, III = 39%, IV = 48%, unknown = 4%. Nine pts are still receiving treatment. The most common treatment-emergent adverse events (AE) were: fatigue (13 pts), diarrhea (9 pts), constipation (8 pts), nausea (8 pts), thrombocytopenia (8 pts), headache (7 pts), anemia (5 pts), dizziness (5 pts), and peripheral neuropathy (5 pts). A total of 6 and 3 pts reported worst grade 3 and 4 AEs, respectively, with no apparent differences between the 2 drug combinations. There were 2 DLTs: grade 3 prolonged Qt at 1.5 mg/kg conatumumab + vorinostat and grade 4 pulmonary embolism at 15 mg/kg conatumumab + bortezomib. An MTD has not been reached. Anti-conatumumb antibodies have not been detected in any pt. After one dose of conatumumab at 1.5, 5, or 15 mg/kg after bortezomib or vorinostat, conatumumab exposures were slightly higher (< 2-fold) than those in the first-in-human monotherapy study, indicating minimal effect of bortezomib or vorinostat on PK of conatumumab. Two pts had a confirmed CR: 1 pt with diffuse large cell lymphoma (1.5 mg/kg vorinostat cohort) at day 97 and 1 pt with nodular sclerosis Hodgkin lymphoma (5 mg/kg vorinostat cohort) at day 169. Thirteen pts had stable disease as their best objective response, 10 of whom had tumor shrinkage (range [based on sum of nodal and extra-nodal at each visit], -1.74% to -68.24%]). Receptor occupancy data will be presented. The combination of conatumumab with either bortezomib or vorinostat did not result in an unacceptable rate of dose-limiting toxicities and showed preliminary evidence of anti-tumor activity in pts with relapsed or refractory lymphoma. The expansion phase in pts with MCL treated with conatumumab plus bortezomib is currently enrolling. Disclosures Younes: Seattle Genetics: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Abbott Oncology: Consultancy; Genentech: Consultancy, Honoraria, Research Funding; Allos Therapeutics : Consultancy; Gloucester Pharm: Consultancy; Amgen: Consultancy, Honoraria, Research Funding; Tiba Oncology: Consultancy; Trubion Pharmaceuticals: Consultancy; Sanofi-Aventis: Honoraria, Research Funding; Methylgene: Honoraria, Research Funding; Pharmion: Honoraria, Research Funding; Xencor: Honoraria, Research Funding; Biogen Idec: Honoraria, Research Funding. Kirschbaum:Merck: Research Funding, Speakers Bureau. Romaguera:Wyeth: Research Funding; Millenium: Research Funding; Celgene: Research Funding. Goyal:Amgen Inc.: Employment, Equity Ownership. Hsu:Amgen Inc.: Employment, Equity Ownership. Hwang:Amgen Inc.: Employment, Equity Ownership. Gorski:Amgen Inc.: Employment, Equity Ownership. Wong:Amgen Inc.: Employment, Equity Ownership. Beaupre:Amgen Inc.: Employment, Equity Ownership.

A Phase I/II Study of Lenalidomide in Combination with Rituximab in Relapsed/Refractory Mantle Cell Lymphoma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2719-2719 ◽  
Author(s):  
Luhua Wang ◽  
Luis Fayad ◽  
Fredrick B. Hagemeister ◽  
Sattva Neelapu ◽  
Felipe Samaniego ◽  
...  
Keyword(s):  
Mantle Cell Lymphoma ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Phase 1 ◽  
Progression Free Survival ◽  
Phase 2 ◽  
Employment Equity ◽  
Mantle Cell ◽  
Equity Ownership ◽  
Grade 3

Abstract Abstract 2719 Poster Board II-695 Background: Rituximab directly targets CD20 positive lymphoma cells while lenalidomide targets the microenvironment. This combination was proven effective in vitro and in vivo in mantle cell lymphoma (Wu et al, Clin Cancer Res 2008; Zhang et al, Am J Hematol 2009). Clinically, lenalidomide (Habermann et al, Br J Haematol 2009) and rituximab have single-agent activity in mantle cell lymphoma (MCL) and may be an effective combination. The goal of our study was to determine the maximum tolerated dose (MTD) in phase 1 and evaluate the efficacy and safety of lenalidomide plus rituximab in patients with relapsed/refractory MCL in phase 2. Methods: Patients with relapsed/refractory MCL received lenalidomide on days 1–21 of every 28-day cycle, and rituximab (375 mg/m2) weekly during cycle 1. Dose escalation was used to determine the MTD with lenalidomide (10 mg, 15 mg, 20 mg, and 25 mg). Dose-limiting toxicity (DLT) was defined as grade 3 or 4 non-hematologic, or grade 4 hematologic adverse events in cycle 1. Phase 2 has reached targeted enrolment with 45 patients treated at MTD. Kaplan-Meier method was used to estimate progression free survival rate and response duration. Median time to event in months with 95% confidence interval was calculated. Of 45 patients treated at the MTD, the median age was 66 (46–85), 91% were males. All patients had received prior rituximab and were enrolled regardless of prior rituximab sensitivity or resistance. Results: The median follow-up time for the censored observations was 11.4 months. Two DLTs occurred at 25 mg in phase 1 (hypercalcemia, non-neutropenic fever); therefore, the MTD was 20 mg. The grade 3–4 non-hematologic events included elevated AST, elevated ALT, fatigue, myalgia, tremors, ataxia, cough, deep vein thrombosis, dyspnea, edema (facial), infection, neuropathy sensory, rash, and respiratory failure. Grade 3–4 hematologic adverse events included neutropenia (37 events), neutropenic fever (4 events), and thrombocytopenia (16 events). There were no responses in patients treated at 10 mg or 15 mg. Thirty six patients (36) were evaluable for response. Nine (9) patients are too early in their treatment and are not yet eligible for response evaluation. Among the 36 evaluable patients, 11 (31%) patients achieved CR, 8 (22%) patients achieved PR, 3 (8%) patients had minor response, 6 (17%) patients had stable disease and 8 (22%) patients had progressive mantle cell lymphoma. The overall response rate (CR + PR) was 53%. Seventy eight (78%) patients achieved stable disease or better and benefited from oral Lenalidomide plus 4 doses of rituximab. The median time to response was 2 months (2–8), and the median duration of response for the 19 patients with CR or PR was 18 months (95% CI: 10.6, NA) (range1–30 months). The median progression free survival for all patients on phase 2 was 14 months (95% CI: 9.8, NA) (ranging from 1–32 months). Conclusion: Oral lenalidomide plus rituximab resulted in durable responses in relapsed/refractory MCL with a favourable toxicity profile. Disclosures: Wang: Celgene: Honoraria, Research Funding. Hagemeister:Celgene Corporation: Consultancy. Samaniego:Celgene Corporation: Research Funding. Yi:Celgene Corporation: Research Funding. Shah:Celgene Corporation: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Elan: Consultancy; Millennium: Research Funding, Speakers Bureau. Bell:Celgene Corporation: Employment, Equity Ownership. Knight:Celgene Corporation: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Zeldis:Celgene: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

Population Pharmacokinetics Study of a New Humanized Anti-CD20 Monoclonal Antibody AME-133v (LY2469298) in Patients with Previously Treated Follicular Lymphoma (FL)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4982-4982
Author(s):  
Damien Cronier ◽  
David Radtke ◽  
Susan P. Carpenter ◽  
James Wooldridge
Keyword(s):  
Monoclonal Antibody ◽  
Follicular Lymphoma ◽  
Dose Group ◽  
Limit Of Detection ◽  
Phase 1 ◽  
Elimination Rate ◽  
Employment Equity ◽  
Mixed Effect ◽  
Previously Treated ◽  
Equity Ownership

Abstract Abstract 4982 Background: AME-133v is a humanized monoclonal antibody that was engineered to have increased affinity to CD20 and mediate antibody-dependent cell-mediated cytotoxicity (ADCC) better than rituximab in vitro. The safety, pharmacokinetics (PK) and preliminary efficacy of AME-133v were assessed in a Phase 1/2 clinical trial in patients with previously treated follicular lymphoma (FL). The objective of this study is to characterize the pharmacokinetics (PK) of AME-133v in the target patient population. Methods: 5 dose levels of AME-133v (2, 7.5, 30, 100, and 375 mg/m2) were tested in a total of 67 patients with previously treated CD20+ FL. AME-133v was administered intravenously in four weekly infusions. Blood samples were obtained pre-dose and 1, 3–5 days after infusion 1, pre-dose and post-dose during infusions 2, 3 and 4, and 1, 5 and 9 weeks after infusion 4. The PK database (399 data points) collected from the patients was analyzed by using the nonlinear mixed-effect model (NONMEM) program. A number of covariates including demographic characteristics and the FcγRIIIa receptor genotype were evaluated for their influence on the AME-133v population PK parameters. Results: Owing to serum concentrations values falling below the limit of detection, the 2 mg/m2 dose group was not included in the analysis. The basic model selected was a two-compartment pharmacokinetic model with first-order elimination. However, a different typical value had to be determined for CL in each dose group. The typical values of V1, Q and V2 were 2.99 L, 0.94 L/day, and 3.31 L, respectively. The typical value for CL was 0.70, 0.53, 0.26, 0.27 L/day-1 for 7.5, 30, 100 and 375 mg/m2, respectively, which indicates a linearization of the elimination rate of AME-133v at doses of 100 mg/m2 and above. Inter-individual variability was moderate to high with CVs of 45.9, 34.1 and 50.0% on CL, V1 and V2, respectively. The only covariate found to influence the PK of AME-133v was BSA which explained 9.6% of the variability observed on V1. The form of the FcγRIIIa receptor was not found to have a significant effect on the PK of AME-133v. Conclusions: The PK of AME-133v were best described by a 2-compartment model. Clearance was found to be dose-dependent with a linearization of the elimination rate at doses of 100 mg/m2 and above. BSA has a statistically significant influence on V1 whereas the FcγRIIIa genotype does not seem to influence the disposition of AME-133v. Disclosures: Cronier: Eli Lilly and Comany: Employment, Equity Ownership. Off Label Use: AME-133v is an investigational agent. Radtke:Eli Lilly and Comany: Employment, Equity Ownership. Wooldridge:Eli Lilly and Company: Employment, Equity Ownership.

Ublituximab (TG-1101), a Novel Glycoengineered Anti-CD20 Monoclonal Antibody, in Combination with Ibrutinib Is Highly Active in Patients with Relapsed and/or Refractory Mantle Cell Lymphoma; Results of a Phase II Trial

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3980-3980 ◽  
Author(s):  
Kathryn Kolibaba ◽  
John M. Burke ◽  
Heather D. Brooks ◽  
Daruka Mahadevan ◽  
Jason Melear ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Monoclonal Antibody ◽  
Mantle Cell Lymphoma ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Employment Equity ◽  
Highly Active ◽  
Mantle Cell ◽  
Equity Ownership ◽  
Anti Cd20

Abstract Introduction: Ublituximab (UTX) is a novel, chimeric monoclonal antibody (mAb) which targets a unique epitope on the CD20 antigen and has been glycoengineered to enhance affinity for all variants of FcγRIIIa receptors, demonstrating greater ADCC than rituximab and ofatumumab. In patients (pts) with rel/ref CLL, the combination of UTX with ibrutinib was well-tolerated and highly active demonstrating an 88% ORR (95% ORR in high-risk CLL) with responses attained rapidly (median time to iwCLL response of 8 weeks). Ibrutinib has demonstrated single agent activity in Mantle Cell Lymphoma (MCL), achieving a 68% ORR (21% CR) in a single arm trial in relapsed or refractory patients (Wang et al, NEJM 2013). Herein we report on the first combination of ibrutinib with a glycoengineered anti-CD20 mAb, UTX, in patients with Mantle Cell Lymphoma (MCL). Methods: Eligible patients had rel/ref MCL with an ECOG PS < 3. Prior ibrutinib treatment was permitted. UTX (900 mg) was administered on Days 1, 8, and 15 in Cycle 1 followed by Day 1 of Cycles 2 - 6. Ibrutinib was started on Day 1 and continued daily at 560 mg. Following Cycle 6, patients came off study but could remain on ibrutinib. Primary endpoints were safety and ORR with an emphasis on early activity with response assessments by CT scan scheduled prior to cycles 3 and 6 only (criteria per Cheson 2007). Results: 15 patients were enrolled: 13 M/2 F, median age 71 yr (range 55-80), ECOG 0/1: 9/6, median prior Tx = 3 (range 1-8), 53% with ≥ 2 prior anti-CD20 therapies, 40% prior bortezomib. Gr 3/4 AE's occurring in at least 5% of patients and at least possibly related to UTX and/or ibrutinib included: neutropenia (13%), fatigue (7%), rash (7%) and atrial fibrillation (7%). Ibrutinib was dose reduced due to an AE in 1 patient (rash) and discontinued in 1 patient due to atrial fibrillation. No UTX dose reductions occurred. All 15 pts are evaluable for response with best response to treatment as follows: 87% (13/15) ORR with 33% (5/15) Complete Response. Three of the CR's occurred at week 8. Of the two patients not achieving an objective response, one patient was stable at first scan and came off treatment prior to second efficacy assessment (ibrutinib related A-Fib) and one patient progressed at first assessment. Responses generally improved from first to second assessment with median tumor reduction of 64% by week 8 and 82% by week 20. Conclusions: Ublituximab, a glycoengineered anti-CD20 mAb, in combination with ibrutinib is both well-tolerated and highly active in pts with rel/ref MCL. Response rate, depth of response, and time to response compare favorably to historical data with ibrutinib alone. A randomized phase 3 trial with ibrutinib +/- ublituximab is currently ongoing in high-risk CLL pts and future studies using this combination in MCL are being evaluated. Disclosures Kolibaba: Janssen: Research Funding; Novartis: Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Research Funding; Gilead: Consultancy, Honoraria, Research Funding; TG Therapeutics: Research Funding; GSK: Research Funding; Genentech: Research Funding; Cell Therapeutics: Research Funding; Celgene: Research Funding; Amgen: Research Funding; Amgen: Research Funding; Acerta: Research Funding. Burke:Gilead: Consultancy; Millenium/Takeda: Consultancy; Seattle Genetics, Inc.: Research Funding; Incyte: Consultancy; Janssen: Consultancy; TG Therapeutics: Other: Travel expenses. Farber:TG Therapeutics, Inc.: Research Funding. Fanning:Celgene and Millennium/Takeda: Speakers Bureau. Schreeder:TG Therapeutics, Inc: Research Funding. Boccia:Incyte Corporation: Honoraria. Sportelli:TG Therapeutics, Inc.: Employment, Equity Ownership. Miskin:TG Therapeutics, Inc.: Employment, Equity Ownership. Weiss:TG Therapeutics, Inc.: Employment, Equity Ownership. Sharman:Roche: Research Funding; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pharmacyclics: Consultancy, Honoraria, Research Funding; Calistoga: Honoraria; Janssen: Research Funding; TG Therapeutics, Inc.: Research Funding; Celgene Corporation: Consultancy, Research Funding.

scholarly journals Frontline Brentuximab Vedotin Plus Cyclophosphamide, Doxorubicin and Prednisone in Patients with Peripheral T-Cell Lymphoma with Less Than 10% CD30 Expression (SGN35-032, Trial in Progress)

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1401-1401
Author(s):  
Deepa Jagadeesh ◽  
Scott Knowles ◽  
Steven M. Horwitz
Keyword(s):  
T Cell ◽  
Research Funding ◽  
Response Rate ◽  
Cell Lymphoma ◽  
Brentuximab Vedotin ◽  
T Cell Lymphoma ◽  
Efficacy And Safety ◽  
Time To Event ◽  
Peripheral T Cell Lymphoma ◽  
Secondary Endpoints

Abstract Background Brentuximab vedotin (BV) was the first antibody-drug conjugate to be approved in multiple cancer types (Gauzy-Lazo 2020). The combination of a CD30-directed monoclonal antibody, a protease-cleavable linker, and the microtubule-disrupting agent monomethyl auristatin E drives the anticancer activity of BV by inducing CD30-targeted cell cycle arrest and apoptosis as well as the bystander effect on adjacent cells (Sutherland 2006, Hansen 2016, Schönberger 2018). In the ECHELON-2 phase 3 clinical trial, BV, cyclophosphamide, doxorubicin, and prednisone (A+CHP) showed efficacy in patients with peripheral T-cell lymphoma (PTCL) across a range of CD30 expression levels, including the lowest eligible level of 10% by immunohistochemistry when compared with patients treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) (Advani 2019). It is hypothesized that A+CHP will demonstrate efficacy in PTCL with &lt;10% CD30 expression because i) clinical responses to BV have occurred in patients with PTCL, cutaneous T-cell lymphoma, or B-cell lymphoma with low (&lt;10%) and undetectable CD30 expression (Jagadeesh 2019) and ii) CD30 expression levels were not predictive of A+CHP responses in non-systemic anaplastic large cell lymphoma (sALCL) (Advani 2019). Study Design and Methods SGN35-032 is a dual-cohort, open-label, multicenter, phase 2 clinical trial (NCT04569032) designed to evaluate the efficacy and safety of A+CHP in patients with non-sALCL PTCL and CD30 expression of &lt;10% on tumor cells. Up to approximately 40 patients will be enrolled in each of the CD30-negative (expression &lt;1%) and the CD30-low (expression ≥1% to &lt;10%) cohorts. Patients will be enrolled based on local results but only patients with CD30 expression &lt;10% per central confirmation will be analyzed for the primary and secondary endpoints. Patients will receive 21-day cycles of A+CHP for 6-8 cycles. Key inclusion criteria include adults with newly diagnosed PTCL, excluding sALCL, per the World Health Organization 2016 classification; CD30 expression &lt;10% by local assessment; and fluorodeoxyglucose-avid disease by positron emission tomography (PET) and measurable disease of at least 1.5 cm by computed tomography (CT), as assessed by the site radiologist. Patients with previous exposure to BV or doxorubicin will not be eligible. The primary endpoint of this trial is objective response rate (ORR) per blinded independent central review (BICR) using the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). Secondary endpoints include ORR by BICR using the modified Lugano criteria (Cheson 2014), complete response rate, progression-free survival (PFS), and duration of response per BICR using the Revised Response Criteria for Malignant Lymphoma (Cheson 2007), overall survival, and safety and tolerability. A PET scan is required at baseline, after Cycle 4, and after the completion of study treatment. Follow-up restaging CT scans will be performed over the next 2 years. In both the CD30-negative and the CD30-low cohorts, efficacy and safety endpoints will be summarized using descriptive statistics to describe continuous variables by cohort. Time-to-event endpoints, such as PFS, will be estimated using Kaplan-Meier (KM) methodology and KM plots will be presented. Medians for time-to-event analyses (e.g., median PFS) will be presented and two-sided 95% confidence intervals will be calculated using the log-log transformation method. Enrollment is planned for 15 US sites and 32 sites across the Czech Republic, France, Italy, and the UK. Disclosures Knowles: Seagen Inc.: Current Employment. Horwitz: ADC Therapeutics, Affimed, Aileron, Celgene, Daiichi Sankyo, Forty Seven, Inc., Kyowa Hakko Kirin, Millennium /Takeda, Seattle Genetics, Trillium Therapeutics, and Verastem/SecuraBio.: Consultancy, Research Funding; Affimed: Research Funding; Aileron: Research Funding; Acrotech Biopharma, Affimed, ADC Therapeutics, Astex, Merck, Portola Pharma, C4 Therapeutics, Celgene, Janssen, Kura Oncology, Kyowa Hakko Kirin, Myeloid Therapeutics, ONO Pharmaceuticals, Seattle Genetics, Shoreline Biosciences, Inc, Takeda, Trillium Th: Consultancy; Celgene: Research Funding; C4 Therapeutics: Consultancy; Crispr Therapeutics: Research Funding; Daiichi Sankyo: Research Funding; Forty Seven, Inc.: Research Funding; Kura Oncology: Consultancy; Kyowa Hakko Kirin: Consultancy, Research Funding; Millennium/Takeda: Research Funding; Myeloid Therapeutics: Consultancy; ONO Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy, Research Funding; Secura Bio: Consultancy; Shoreline Biosciences, Inc.: Consultancy; Takeda: Consultancy; Trillium Therapeutics: Consultancy, Research Funding; Tubulis: Consultancy; Verastem/Securabio: Research Funding.

scholarly journals Ponatinib Efficacy and Safety in Patients with the T315I Mutation: Long-Term Follow-up of Phase 1 and Phase 2 (PACE) Trials

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4552-4552 ◽  
Author(s):  
Michael J. Mauro ◽  
Jorge E. Cortes ◽  
Andreas Hochhaus ◽  
Michele Baccarani ◽  
Timothy P. Hughes ◽  
...  
Keyword(s):  
Research Funding ◽  
Progressive Disease ◽  
Phase 1 ◽  
Efficacy And Safety ◽  
Employment Equity ◽  
Long Term Follow Up ◽  
T315i Mutation ◽  
Equity Ownership

Abstract Background: Resistance to tyrosine kinase inhibitors (TKIs) in patients (pts) with chronic myeloid leukemia (CML) and Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) is frequently caused by mutations in the BCR-ABL kinase domain. Ponatinib is the only approved oral TKI that inhibits the T315I mutant, which is uniformly resistant to other TKIs. Here we report long-term follow-up of the efficacy and safety of ponatinib in pts with the T315I mutation at baseline from the Phase 1 (Ph1) and PACE trials. Methods: The Ph1 trial (NCT01207440) evaluated safety and anti-leukemic activity of ponatinib (2-60 mg qd) in pts with CML or Ph+ ALL (N=81); the PACE trial (NCT00660920) evaluated efficacy and safety of ponatinib (45 mg qd) in CML and Ph+ ALL pts (N=449) resistant/intolerant to dasatinib or nilotinib or with the T315I mutation. Data reported are for pts with the T315I mutation at baseline, detected by Sanger sequencing at a central lab. Results: The Ph1 and PACE trials included 19 (29%) and 128 (29%) pts with the T315I mutation, respectively. Median age and median time since diagnosis were 47 and 2.7 years for Ph1, and 53 and 3.6 years for PACE.Pts were heavily pretreated: 89% in Ph1 and 84% in PACE had received ≥2 prior TKIs. As of Jan 6, 2014, median follow-up was 42 (1-59) months in Ph1, and 20 (0.1-40) months in PACE; 58% Ph1 (92% CP-CML) and 33% PACE (52% CP-CML) pts remained on study. Most-common reasons for discontinuation: administrative decision (16%) and progressive disease (16%) for Ph1, and progressive disease (31%) and adverse events (AEs; 13%) for PACE. Of the pooled chronic phase (CP)-CML pts, 75%, 72%, and 61% achieved MCyR, CCyR, and MMR, respectively, with deeper responses (MR4, MR4.5) observed in over a third of the pts (Table). MaHR was achieved in 58%, 27% and 38% of pooled AP-CML, BP-CML and Ph+ ALL pts, respectively. For Ph 1 CP-CML pts, 3-year CCyR duration estimates were 80%. For PACE CP-CML pts, 2-year MCyR/CCyR duration, PFS and OS estimates were 93%/79%, 72% and 82%, respectively. Only 1 CP-CML pt in PACE lost MCyR and 1 transformed to AP-CML. For AP-CML, BP-CML, and Ph+ ALL, estimated OS/PFS at 2 years was 69%/54%, 14%/10%, and 10%/N/A, respectively. The most frequent treatment-emergent AEs (TEAEs) observed in Ph1 CP-CML pts were dry skin (83%), rash (83%), arthralgia (75%), fatigue (75%), headache (67%), abdominal pain (58%), hypertension (58%), hypertriglyceridemia (58%), myalgia (58%), and nausea (58%). None of the 19 serious TEAEs that occurred in Ph1 CP-CML pts occurred in >1 pt. The most common (≥25%) TEAEs in PACE CP-CML pts were rash (48%), dry skin (42%), headache (41%), abdominal pain (39%), nausea (36%), constipation (33%), fatigue (33%), thrombocytopenia (28%), myalgia (28%), hypertension (27%), arthralgia (25%), and upper respiratory tract infection (25%). Most common (≥5 %) serious TEAEs in PACE CP-CML pts were acute myocardial infarction (8%), pancreatitis (8%), atrial fibrillation (6%), coronary artery disease (6%), congestive cardiac failure (5%), pneumonia (5%), cerebral infarction (5%), pyrexia (5%), increased lipase (5%), and dyspnea (5%). Arterial thrombotic events occurred in 1 (8%) Ph1, and 20 (31%) PACE pts. Venous thromboembolic events occurred in 1 (8%) Ph1, and 3 (5%) PACE pts. Despite the higher median dose intensity for T315I CP-CML pts (38 vs 30.8 mg/day overall CP-CML) in PACE, the safety profiles were similar. For CP-CML pts in PACE, responses achieved by 12 months were generally maintained after dose reduction primarily to manage AEs: 100% maintained MCyR; 100% maintained CCyR, and 79% maintained MMR. Conclusions: In Ph+ leukemia pts with the T315I mutation, where effective treatment options are limited, ponatinib continued to exhibit deep and durable responses with up to 6 years follow-up. Dose reductions to manage AEs did not impact maintenance of cytogenetic responses. The response rates and safety profile of T315I pts were comparable to, if not better than, those observed in the overall population of refractory CML and Ph+ ALL pts in ponatinib clinical trials. Table. Responses at Any Time in Ponatinib Treated Pts with T315I Mutation Phase 1 PACE Phase 1 and PACE Pooled n (%) n (%) n (%) CP-CML N=12 N=64 N=76 MCyR 11 (92) 46 (72) 57 (75) CCyR 10 (83) 45 (70) 55 (72) MMR 9 (75) 37 (58) 46 (61) MR4 7 (58) 25 (39) 32 (42) MR4.5 4 (33) 21 (33) 25 (33) AP-CML N=1 N=18 N=19 MaHR 0 11 (61) 11 (58) BP-CML N=2 N=24 N=26 MaHR 0 7 (29) 7 (27) Ph+ ALL N=4 N=22 N=26 MaHR 2 (50) 8 (36) 10 (38) Disclosures Mauro: ARIAD Pharmaceuticals, Inc.: Consultancy. Cortes:ARIAD, BMS, Novartis, Pfizer, Teva: Consultancy, Research Funding. Hochhaus:ARIAD Pharmaceuticals, Inc.: Research Funding. Baccarani:ARIAD, Novartis, BMS: Consultancy; ARIAD, Novartis, BMS, Pfizer, Teva: Honoraria; ARIAD, Novartis, BMS, Pfizer, Teva: Speakers Bureau. Hughes:Novartis, BMS, ARIAD: Honoraria, Research Funding. Guilhot:ARIAD Pharmaceuticals, Inc.: Honoraria. Deininger:BMS, Novartis, Celgene, Genzyme, Gilead: Research Funding; BMS, ARIAD, Novartis, Incyte, Pfizer: Advisory Board, Advisory Board Other; BMS, ARIAD, Novartis, Incyte, Pfizer: Consultancy. Kantarjian:ARIAD Pharmaceuticals, Inc., Pfizer, Amgen: Research Funding. Shah:ARIAD Pharmaceuticals, Inc., BMS: Research Funding. Flinn:ARIAD Pharmaceuticals, Inc.: Research Funding. Lustgarten:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Rivera:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Haluska:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Clackson:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Talpaz:ARIAD Pharmaceuticals, Inc., BMS, Sanofi, Incyte, Pfizer: Research Funding.

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